Process for preparing substituted benzoyl cyanide amidinohydrazones

ABSTRACT

The present invention provides a process for preparing a compound of the general formula (I):  
                 
 
     wherein R 1  to R 5  are independently selected from hydrogen, halogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl or C 1-6  alkoxy, all optionally substituted by one or more of halogen, hydroxy and aryl groups, as well as being independently selected from amino, mono- or disubstituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and alkylthio groups, which process comprises reacting a compound of the general formula (II):  
                 
 
     wherein R 1  to R 5  are as defined in formula (I), with aminoguanidine bicarbonate in a mixture of a water-soluble solvent and polyphosphoric acid.

FIELD OF THE INVENTION

[0001] The present invention relates to a method for preparingsubstituted benzoyl cyanide amidinohydrazones. More particularly, thepresent invention pertains to the preparation of these compounds by areaction of substituted benzoyl cyanides with aminoguanidine in thepresence of polyphosphoric acid.

BACKGROUND OF THE INVENTION

[0002] It is known that certain 3,5-diamino-6-(substitutedphenyl)-1,2,4-triazines are active in the treatment of CNS disorders,such as psychiatric and neurological disorders, and are also useful asanticonvulsants, for example in the treatment of epilepsy. Thesetriazines are also non-depressant at therapeutic dose levels and aretherefore advantageous as compared with depressant anti-epileptics suchas phenobarbitone.

[0003] A particularly preferred compound of this type is3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (e.g. European Patent21121).

[0004] A known process for preparing 3,5-diamino-6-(substitutedphenyl)-1,2,4-triazines, comprises reacting substituted benzoyl cyanideswith aminoguanidine in aqueous solutions of strong acids such as nitricacid (J. A. Settepani and A. B. Borkovec, J. Heterocycl. Chem., 1966, 3,188, U.S. Pat. Nos. 3,637,688; 4,486,354; 4,602,017; 4,649,139, R. W. A.Rees et al, J. Med. Chem., 1972, 15, 859; European Patent Nos. 21,121;142,306; 247,892, Israeli Patent Nos. 60,201; 73,332; 82,710) andsulfuric acid (European Patent No. 247,892, Israeli Patent No. 82,710)to produce amidinohydrazone of the general formula (A):

[0005] wherein R₁ is halogen, C₁₋₄ alkyl or trifluoromethyl, R₂ ishydrogen, halogen, C₁₋₄ alkyl or trifluoromethyl, or R₁ and R₂ form a—CH═CH—CH═CH— group optionally substituted by a halogen atom or a C₁₋₄alkyl or trifluoromethyl group, R₃ and R₄ are independently selectedfrom hydrogen, halogen, C₁₋₄ alkyl or trifluoromethyl groups and R₅ ishydrogen, methyl or fluorine.

[0006] 3,5-Diamino-6-(substituted phenyl)-1,2,4-triazines (compounds ofthe general formula (B):

[0007] wherein R₁-R₅ are as hereinbefore defined) are obtained by ringclosure of a compound of the formula A.

[0008] The ring closure is normally carried out by refluxing in analcohol, such as methanol, ethanol, 1-propanol and the like, in thepresence of a strong base, such as sodium hydroxide, potassium hydroxideand the like.

[0009] However, the reaction of substituted benzoyl cyanides withaminoguanidine in the aqueous solutions of strong acids is very slow andusually from 2 to 21 days are required to complete this reaction. On theother hand, substituted benzoyl cyanides are hydrolyzed at the reactionconditions, and overall yield of the triazines is low (from 2 to 41%)(Table). TABLE Yield of the Tem- compound Compounds perature Time of ofthe of the Solvent of the of the the formula formula (A) reactionreaction reaction (B) R⁶═R⁷═Cl a) DMSO and 8N 25° C.  7 days 15.6%*R⁸═R⁹═R¹⁰═H aqueous nitric acid b) Acetonitrile 20-30° C. 48 hours41%**  and 63% aqueous sulfuric acid R⁶═R⁷═R⁹═Cl DMSO and 8N 20-30° C.21 days  1.6%* R⁸═R¹⁰═H aqueous nitric acid R⁶═R⁸═Cl DMSO and 8N 25° C.24 hours  8%*** R⁷═R⁹═R¹⁰═H aqueous nitric acid R⁷═R⁸═Cl DMSO and 8N 25°C. 24 hours 23%*** R⁶═R⁹═R¹⁰═H aqueous nitric acid R⁸═Cl DMSO and 8N 25°C. 24 hours 37%*** R⁶═R⁷═R⁹═ aqueous nitric R¹⁰═H acid

SUMMARY OF THE INVENTION

[0010] As a result of research to solve the drawbacks of the prior artmethods, the present inventors have found the method for preparing thesubstituted benzoyl cyanide amidinohydrazones by a reaction ofsubstituted benzoyl cyanides with aminoguanidine in a mixture ofpolyphosphoric acid and a solvent in the absence of water whichminimizes the hydrolysis of the benzoyl cyanides.

[0011] According to the present invention substituted benzoyl cyanideamidinohydrazones can be prepared in higher yield after the reaction ofsubstituted benzoyl cyanide with aminoguanidine in a mixture ofpolyphosphoric acid and acetonitrile for 24 hours.

[0012] Other objects and advantages of the present invention will beapparent from the following description.

DETAILED DESCRIPTION OF THE INVENTION

[0013] More specifically, the present invention provides a process forpreparing a compound of the general formula (I):

[0014] wherein R₁ to R₅ are independently selected from hydrogen,halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₁₋₆ alkoxy, alloptionally substituted by one or more of halogen, hydroxy and arylgroups, as well as being independently selected from amino, mono- ordisubstituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl andalkylthio groups, which process comprises reacting a compound of thegeneral formula (II):

[0015] wherein R₁ to R₅ are as defined in formula (I), withaminoguanidine bicarbonate in a mixture of a water-soluble solvent andpolyphosphoric acid.

[0016] Suitably the total number of carbon atoms in R₁ to R₅ is lessthan eight.

[0017] The phenyl ring will suitably contain up to three substituentsand preferably one or two substituents.

[0018] R₁ to R₅ are preferably independently selected from halogen andhydrogen. Particularly preferred substitutions are 4 or 2,3 or 2,4 or3,4 mono- or di- halo (especially chloro).

[0019] Preferred compounds are:

[0020] 4-Chlorobenzoyl cyanide amidinohydrazone,

[0021] 2,3-Dichlorobenzoyl cyanide amidinohydrazone,

[0022] 2,4-Dichlorobenzoyl cyanide amidinohydrazone,

[0023] 3,4-Dichlorobenzoyl cyanide amidinohydrazone.

[0024] The preparation of the compounds of the formula (II) is analogousto that described in the literature, i.e. U.S. Pat. No. 3,637,688; R. W.A. Rees et al, J. Med. Chem., 1972, 15, 859.

[0025] The amount of aminoguanidine bicarbonate is preferable more thanone equivalent and more preferable 1.5 molar equivalents relative tocompound of the formula (II).

[0026] The amount of polyphosphoric acid is preferably from 4 to 8 g,and more preferably 5.5 g to one gram of the compound of formula (II).

[0027] The reaction solvents are preferably water-soluble solvents suchas acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane (monoglyme),2-methoxyethyl ether (diglyme) and the like and more preferablyacetonitrile.

[0028] The amount of the reaction solvent is preferably from 2 to 8 ml,and more preferably 5 ml to one gram of the compound of the formula(II).

[0029] The reaction temperature may be chosen from ambient temperatureto the reflux temperature of the solvent, and more preferably thetemperature is between 50-70° C.

[0030] Since the progress of the reaction can be monitored by using highperformance liquid chromatography, the reaction may be stopped after thedisappearance of the starting material.

[0031] Although amidinohydrazones of the formula (I) exist as twoisomers (E- and Z-forms), for the purpose of the present invention,these compounds may exist as either of the isomers or as a mixturethereof.

[0032] After completion of the reaction, water is added to the reactionmixture to obtain a clear homogeneous mixture. The mixture is dropped towater, and a colourless precipitate is collected by filtration to obtaina wet phosphate of the compound of the formula (I).

[0033] The wet phosphate of the compound of the formula (I) is added toan aqueous alkali solution, e.g., sodium hydroxide and the like, and themixture is stirred at ambient temperature for one hour. A precipitate isthen collected by filtration, washed with water and dried at 80° C. togive a free base of the compound of the formula (I).

[0034] Triazines of the general formula (III):

[0035] wherein R₁ to R₅ are as defined in the formula (I), can beobtained from the compound of the formula (I) by a procedure similar tothat described in the literature, i.e. Beyer et al, Chem. Ber. 1960, 93,2209; J. A. Settepani and A. B. Borkovec, J. Heterocycl. Chem., 1966, 3,188, U.S. Pat. No. 3,637,688; R. W. A. Rees et al, J. Med. Chem., 1972,15, 859; European Patent Nos. 21,121; 247,892.

[0036] According to the present invention, the compounds of the formula(I) can be obtained in high yield from the compound of the formula (II)by using polyphosphoric acid and simple procedures.

[0037] The present invention will be concretely illustrated by Exam,which show the method for preparation of the compound of formula (I).

[0038] While the invention will now be described in connection withcertain preferred embodiments in the following examples so that aspectsthereof may be more fully understood and appreciated, it is not intendedto limit the invention to these particular embodiments. On the contrary,it is intended to cover all alternatives, modifications and equivalentsas may be included within the scope of the invention as defined by theappended claims. Thus, the following examples which include preferredembodiments will serve to illustrate the practice of this invention, itbeing understood that the particulars shown are by way of example andfor purposes of illustrative discussion of preferred embodiments of thepresent invention only and are presented in the cause of providing whatis believed to be the most useful and readily understood description offormulation procedures as well as of the principles and conceptualaspects of the invention.

EXAMPLE 1 Preparation of 2,3-Dichlorobenzoyl cyanide amidinohydrazone

[0039] a) Reactor (0.5 L) was charged under nitrogen with acetonitrile(200 ml) and polyphosphoric acid (220 g), and the mixture was stirredfor 0.5 hour to obtain an emulsion. Solid 2,3-dichlorobenzoyl cyanide(41 g, 0.2 mole; assay 97.5%) was added to the emulsion. Aminoguanidinebicarbonate (41 g, 0.3 mole; assay 99.0%) was added to the mixture in 5equal portions during 2 hours at 30-40° C. The reaction mixture wasstirred at 50° C. during 22 hours. Water (40 ml) was then added to thereaction mixture to obtain a clear homogeneous mixture. The mixture wasdropped to water at slow stirring for 0.5 hour, and the precipitate wascollected by filtration to give wet phosphate salt of2,3-dichlorobenzoyl cyanide amidinohydrazone.

[0040] The wet phosphate salt was added at ambient temperature to 2.5%aqueous sodium hydroxide solution (500 ml), and the mixture was stirredfor 0.5 hour. The precipitate was collected by filtration, washedthoroughly with water and dried at 80° C. overnight to give 43.0 g (84%yield) of 2,3-dichlorobenzoyl cyanide amidinohydrazone base.

[0041] m.p. 221-222° C. (uncorrected) (after dissolution intetrahydrofuran, filtration of the solution and removal of the solventto dryness in vacuo).

[0042]¹H NMR (DMSO-d₆): δ (ppm)=6.7 (4H, s, NH), 7.3-7.7 (3H, m, ArH).¹³C NMR (DMSO-d₆): δ (ppm)=113.88 and 114.53 (C≡N, d, E- and Z-forms ofthe hydrazone), 128.24, 129.53 and 130.10 (3C—H from Ar), 163.64[—NH—C(NH₂)═NH]. MS (FAB): m/z 256 (MH⁺). Analysis: Calcd. forC₉H₇Cl₂N₅: C, 42.21; H, 2.75; N, 27.35, found: C, 42.12; H, 2.77; N,27.80.

[0043] b) The title compound was obtained in 67% yield after carryingout the reaction of 2,3-dichlorobenzoyl cyanide with aminoguanidine in amixture of monoglyme and polyphosphoric acid.

EXAMPLE 2 Preparation of3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine

[0044] a) The 2,3-dichlorobenzoyl cyanide amidinohydrazone base (43.0 g)obtained in Example 1(a) was heated under reflux in 1-propanol (560 ml)for two hours. The hot solution was filtered off, and the filtrate wascooled to 10° C. The crystals were collected by filtration,recrystallized from 1-propanol (490 ml) and dried at 100° C. to give3,5-diamino-6-(2,3,-dichlorophenyl)-1,2,4-triazine (34.5 g).

[0045] The 1-propanol was evaporated to dryness in vacuo from the twofiltrates, and the residue was recrystallized from 1-propanol to give4.0 g of the title compound.

[0046] Total yield (from 2,3-dichlorobenzoyl cyanide): 38.5 g (75.2%),m.p. 216-218° C. (uncorrected).

[0047]¹H NMR (DMSO-d₆): δ (ppm)=6.16 (2H, s, NH), 6.45 (2H, br s, NH),7.2-7.7 (3H, m, ArH). ¹³C NMR (DMSO-d₆): δ (ppm)=129.26, 131.35 and131.51 (3 C—H from Ar), 155.114 [C—C(NH₂)═N—], 162.95 [═N—C(NH₂)═N—]. MS(FAB): m/z 256 (MH⁺).

[0048] b) Wet phosphate obtained by the procedure similar to that ofExample 1(a) from 200 g (0.959 mole; assay: 95.91%) of2,3-dichlorobenzoyl cyanide was added to 1-propanol (2.0 L), and themixture was heated to 65° C. at stirring. 45% Aqueous sodium hydroxidesolution (185 ml) was then added to this mixture to produce pH 10, andthe mixture was heated under reflux for two hours. The water phase wascollected, and the organic phase was cooled to 10° C. The colourlesscrystals were collected by filtration, recrystallized from 1-propanol(2.0 L) (the hot solution was filtered) and dried at 100° C. to give 160g of the title compound.

[0049] An additional 20.0 g of the title compound was obtained from thefiltrates. Total yield (from 2,3-dichlorobenzoyl cyanide): 180 g(73.3%).

[0050] c) The title compound was obtained in 60% total yield (from2,3-dichiorobenzoyl cyanide) from 2,3-dichlorobenzoyl cyanideamidinohydrazone obtained in Example 1(b).

EXAMPLE 3 Preparation of 2,4-dichlorobenzoyl cyanide amidinohydrazone

[0051] The title compound was prepared as in Example 1(a). Yield: 65%.¹H NMR (DMSO-d₆): δ (ppm)=6.70 (4H, s, NH), 7.4-7.8 (3H, m, ArH). ¹³CNMR (DMSO-d₆): δ (ppm)=114.16 and 114.65 (C═N, d, E- and Z-forms of thehydrazone), 128.06, 130.05 and 132.22 (3 C—H from Ar), 163.87[—NH—C(NH₂)═NH]. MS (FAB): m/z 256 (MH⁺).

EXAMPLE 4 Preparation of3,5-Diamino-6-(2,4-dichlorophenyl)-1,2,4-triazine

[0052] The title compound was prepared as in Example 2(a) from2,4-dichlorobenzoyl cyanide amidinohydrazone obtained in Example 3. Thesolvent for ring closure was a mixture of 1-propanol anddimethylsulfoxide (5:1). Total yield (from 2,4-dichlorobenzoyl cyanide):55%; m.p. 220-222° C. (uncorrected).

[0053]¹H NMR (DMSO-d₆): δ (ppm)=6.40 (2H, s, NH), 6.66 (2H, br s, NH),7.1-7.8 (3H, m, ArH). ¹³C NMR (DMSO-d₆): δ (ppm)=127.60, 129.04 and133.19 (3 C—H from Ar), 154.21 [C—C(NH₂)═N—], 161.98 [═N—C(NH₂)═N—]. MS(FAB): m/z 256 (MH⁺).

EXAMPLE 5 Preparation of 3,4-Dichlorobenzoyl cyanide amidinohydrazone

[0054] The title compound was prepared as in Example 1(a). Yield: 86%.

[0055]¹H NMR (DMSO-d₆): δ (ppm)=7.28 (4H, s, NH), 7.5-8.3 (3H, m, ArH).¹³C NMR (DMSO-d₆): δ (ppm)=112.44 and 117.20 (C≡N, d, E- and Z-forms ofthe hydrazone), 125.20, 126.06 and 131.95 (3 C—H from Ar), 160.99[—NH—C(NH₂)═NH]. MS (FAB): m/z 256 (MH⁺).

EXAMPLE 6 Preparation of3,5-Diamino-6-(3,4-dichlorophenyl)-1,2,4-triazine

[0056] The title compound was prepared as in Example 2(a) from3,4-dichlorobenzoyl cyanide amidinohydrazone obtained in Example 5. Thesolvent for the ring closure was a mixture of 1-propanol and dimethylsulfoxide (1:1). Total yield (from 3,4-dichlorobenzoyl cyanide): 76%;m.p. 222-224° C. (uncorrected).

[0057]¹³C NMR (DMSO-d₆): δ (ppm)=128.6, 130.24 and 130.83 (3 C—H fromAr), 155.02 [C—C(NH₂)═N—], 158.99 [═N—C(NH₂)═N—]. MS (FAB): m/z 256(MH⁺).

EXAMPLE 7 Preparation of 4-Chlorobenzoyl cyanide amidinohydrazone

[0058] The title compound was prepared as in Example 1(a). Yield: 80%.

[0059]¹H NMR (DMSO-d₆): δ (ppm)=6.70 (4H, s, NH), 7.2-8.0 (4H, m, ArH).¹³C NMR (DMSO-d₆): δ (ppm)=113.49 and 116.79 (C≡N, d, E- and Z-forms ofthe hydrazone), 125.95 and 128.44 (4 C—H from Ar), 163.90[—NH—C(NH₂)═NH]. MS (FAB): m/z 222 (MH⁺).

EXAMPLE 8 Preparation of 3,5-Diamino-6-(4-chlorophenyl)-1,2,4-triazine

[0060] The title compound was prepared as in Example 2(a) from4-chlorobenzoyl cyanide amidinohydrazone obtained in Example 7. Thesolvent for the ring closure was a mixture of 1-propanol and dimethylsulfoxide (4:1). Total yield (from 4-chlorobenzoyl cyanide): 72%; m.p.219-221° C. (uncorrected).

[0061]¹H NMR (DMSO-d₆): δ (p)=6.43 (2H, s, NH), 6.73 (2H, br s, NH),7.3-7.7 (4H, m, ArH). ¹³C NMR (DMSO-d₆): δ (ppm)=128.69 and 129.87 (4C—H from Ar), 154.32 [C—C(NH₂)═N—], 161.55 [═N—C(NH₂)═N—]. MS (FAB): m/z222 (MH⁺).

[0062] It will be evident to those skilled in the art that the inventionis not limited to the details of the foregoing illustrative examples andthat the present invention may be embodied in other specific formswithout departing from the essential attributes thereof, and it istherefore desired that the present embodiments and examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing description, and all changes which come within the meaning andrange of equivalency of the claims aretherintended to be embraced ther.

What is claimed is:
 1. A process for preparing a compound of the generalformula (I):

wherein R₁ to R₅ are independently selected from hydrogen, halogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₁₋₆ alkoxy, all optionallysubstituted by one or more of halogen, hydroxy and aryl groups, as wellas being independently selected from amino, mono- or disubstitutedamino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and alkylthiogroups, which process comprises reacting a compound of the generalformula (II):

wherein R₁ to R₅ are as defined in formula (I), with aminoguanidinebicarbonate in a mixture of a water-soluble solvent and polyphosphoricacid.
 2. A process according to claim 1 wherein the amount ofaminoguanidine bicarbonate is more than 1 equivalent per 1 equivalent ofthe compound of formula (II).
 3. A process according to claim 1 whereinthe amount of polyphosphoric acid is from 4 to 8 g per one gram of thecompound of formula (II).
 4. A process according to claim 1 wherein saidwater-soluble solvent is acetonitrile.
 5. A process according to claim 1wherein the reaction of the compound of formula (II) with aminoguanidinebicarbonate is carried out at a temperature of about 25-150° C.
 6. Aprocess according to claim 1 wherein the compound of formula (I) is2,3-Dichlorobenzoyl cyanide amidinohydrazone.